Human skin is a-primary target of nonionizing electromagnetic radiation in the ultraviolet, visible, and infrared ranges, and consists of three distinct layers: the stratum corneum, the epidermis, and the dermis. The epidermis and dermis contain several molecules known as chromophores, that are capable of absorbing light or UV radiation (UVR). The main chromophores in human skin include such molecules as nucleic acids, aromatic amino acids, proteins, porphyrins, carotenoids, steroids, and quinones (Mary S. Matsui and Vincent A. DeLeo, Skin Cancer: Mechanisms and Human Relevance Chp. 4, 22 (Hasan Mukhtar ed., 1995)).
The UV spectrum is divided into A, B, and C ranges. The UVC range extends from wavelengths between 200 and 290 nm. The UVB spectrum includes wavelengths between 290 and 320 nm, and is generally known as the sunburn spectrum because it produces erythema in human skin. UVA radiation includes wavelengths between 320 to 400 nm. Atmospheric ozone absorbs all UVC and much of the UVB, so that the spectrum of UV radiation at the earth's surface consists primarily of UVA. The depth to which a photon penetrates in vivo is related to its wavelength. Thus, most UVB radiation transmitted through the ozone layer is absorbed within the first 0.03 mm of the epidermis, whereas one third of UVA radiation penetrates to a depth of 0.1 mm (Hardie et al., Surgery 87:177 (1980)).
When the skin is exposed to UVR, energy transferred to chromophores from the absorbed radiation may result in molecular reorganization and/or interaction with nearby biomolecules. For example, after UVR absorption, DNA may form dipyrimidine lesions, such as cyclobutane pyrimidine dimers. In turn, characteristic mutations result, e.g., mutations in p53, that have been shown to be important in producing non-melanoma skin cancer. (A. Ziegler et al., Nature 372:773-776 (1994)). Furthermore, the UV-induced conversion of urocanic acid from the trans to cis isomer has been linked to the subsequent development of non-melanoma skin cancers (Craig A. Elmets et al., Skin Cancer: Mechanisms and Human Relevance Chp. 18, 230 (Hasan Mukhtar ed., 1995)).
Further insight into UV-induced skin tumor formation has been gained from studies in rodents. UV-induced skin tumors stimulate a strong immune response. If UV-induced tumors are implanted into normal, genetically identical mice, they are promptly rejected by the host immune-system and the animals survive. If the same tumor is implanted into mice that have been exposed to subcarcinogenic doses of UVR, immunological destruction of the tumor does not occur. These results indicate that UVR produces mutations in skin cells and facilitates tumor growth by impairing immune surveillance. The presence of both deficiencies is necessary for clinically apparent skin cancers to develop (J. T. Krutmann and C. A. Elmets eds. (1995). Photoimmunology. Oxford: Blackwell Scientific).
Currently marketed sunscreens function either as ultraviolet (UV) filters or UV blocks. UV blocks, such as TiO2 and ZnO, as well as derivatives of other metal-oxides, form a physical barrier that scatters UV light. These UV blocks offer the most comprehensive sunscreen protection, blocking the full spectrum of UVA and UVB light. However, the most commonly used sunscreens are UV filters, which are typically organic compounds. A disadvantage of UV filters is that each organic compound has a limited range of maximum UV absorptivity, rendering each reagent better suited for either UVA protection or UVB protection, but not both.
The UV-induced mouse tumor model has proven very useful not only in gaining mechanistic understanding of skin tumor formation, but also in determining if topical products promote or inhibit the formation of UV-induced tumors. A standard UV carcinogenicity model accepted for the testing of topical pharmaceuticals employs the albino hairless Crl:SKH1-hr BR mouse (P. D. Forbes et al., Photobiology. 663-669 (E. Riklis ed., 1991)).
After administration of a topical formulation, experimental protocols typically instruct that mice be irradiated once daily, five days per week, for 40 weeks. Intensity and cumulative UV radiation dose is measured in Robertson-Bergen Units (RBU). The RBU is a measure of biological effectiveness for UVR, with 400 RBU being approximately one minimal erythema dose in previously untanned human skin, i.e., about 30 mJ/cm2 in a sun-sensitive skin type I or II. Mouse carcinogenicity studies are completed at 600 RBU per week because this produces an appropriate tumor mean latent period for comparison with test article treated and untreated controls. At this radiation level, about half of the untreated animals will have a first perceptible tumor by week forty-one. A higher control UVR level of 1200 RBU per week results in a significant reduction in the median tumor latent period. At this radiation dose, about half of the untreated animals will have a first perceptible tumor by week twenty-four. Animals continue to be observed for 12 weeks after 40 weeks of product application to provide a total of 52 weeks of tumor data.
At least two common topical therapies promote tumor formation in this UV induced mouse carcinogenicity model. Benzoyl peroxide and retinoids such as tretinoin, which are commonly used to treat acne, promote the formation of skin tumors compared to untreated or vehicle controls. (Physicians Desk Reference, 56th Edition, Medical Economics Company, Inc., Montvale N.J., (2002)). While many topical products containing these actives are currently in use, the patients who use them are strongly encouraged to avoid sun exposure on their face after using the product. However, significantly shielding the face from sun exposure, especially for young adults, is virtually impossible for products that are often used twice daily.
U.S. Pat. Nos. 6,113,888 to Castro et al.; U.S. Pat. No. 6,200,964 to Singleton et al.; and U.S. Pat. No. 6,231,837 to Stroud et al. describe topical compositions that contain therapeutics. However, the therapeutic is not included to provide protection from ultraviolet radiation. If UVR protection is desired, sunscreens are added to the formulations.
Topical compositions including dapsone have been described in U.S. Pat. Nos. 5,863,560 and 6,060,085 to Osborne, and U.S. application Ser. No. 10/081,050 to Osborne, which are herein incorporated by reference in their entirety. However, these compositions were formulated to treat acne, not to prevent skin damage from UV radiation.
Therefore, new compositions that protect against UV-induced skin damage are needed.